Field of the Invention
The invention relates to propellant mixtures and their use in pharmaceutical aerosols for pulmonary application.
Due to their technical benefits, fluorochlorohydrocarbons (CFCs) are currently still used as coolants in refrigeration and air-conditioning plants and as propellant gases in metered dose aerosols. Their environmentally harmful effects, particularly in terms of destruction of the ozone layer in the earth's atmosphere, have also prompted extensive research into harmless substitutes. In this way, there is also a need, in the field of aerosol production, to develop innovative and environmentally compatible propellants and manufacturing processes for aerosols.
A process of CFC-free aerosol preparation for use in special inhalers, "MDIs" (metered dose inhalers) is disclosed in U.S. Pat. No. 5,190,029. 1,1,1,2-tetrafluoroethane, also known as R 134a, is used as a propellant either on its own or mixed with various other hydrocarbons. The active pharmaceutical ingredient is salbutamol; oleic acid is added as a surface-active additive. The density, vapor pressures and other relevant properties of the formulations were measured, according to which just 22% to 39% of the generated aerosol particles have an aerodynamic diameter of less than or equal to 11.2 .mu.m. WO 9304671 describes an aerosol composed of a medicinal agent, a glycerophosphatide and a propellant gas or propellant gas mixture of n-butane, dimethyl ether and propane. The presence of glycerophosphatides increases the medicinal agent's solubility in the propellant gas. By suitably adjusting the proportions of the various components, the system forms a homogeneous solution, i.e. not a suspension. This application document does not indicate whether sufficiently fine particles can be produced from this homogeneous solution.
Several patent applications and patent specifications propose using 1,1,1,2-tetrafluoroethane (R 134a, CH.sub.2 FCF.sub.3) and 1,1,1,2,3,3,3-heptafluoropropane (R 227, CF.sub.3 CHFCF.sub.3) as alternative propellants. Such documents include e.g. DE 4123663, DE 4038203, EP 526002, EP 512502, EP 518601, EP 518600, EP-A-372777, U.S. Pat. Nos. 5,182,097, 5,185,094, 5,118,494, 5,126,123, 5,190,029, 5,202,110, WO 9104011, WO 9200062, WO 9211190 and WO 9206675. Although these compounds do not contain chlorine and consequently do not have any harmful effects on the ozone layer of the earth's atmosphere, they exhibit a considerable greenhouse potential (Michael E. Whitham et al.: Respiratory Drug Delivery IV, 1994, 203; Pamela S. Zurer: Chem. En. News, 15 (11), 1993, 12).
The commercially available CFC metered dose aerosols exist in the form of a suspension of the active ingredient in the propellant. One or more surfactants are used to suspend a pharmaceutical in the propellant gas mixture which normally comprises dichlorodifluoromethane (R12), trichlorofluoromethane (R11) and 1,2-dichlorotetrafluoroethane (R114). The most commonly used surfactants are e.g. sorbitan trioleate, oleic acid and lecithin. These substances do however suffer from the drawback that they are insoluble in R134a and R227 (Peter R. Byron, et al.: Respiratory Drug Delivery IV, 1994, 237; Ashley Woodcock: Journal of Aerosol Medicine, 8 (Suppl. 2) 1995, p. 5).
In chemical engineering, compressed gases have already been in use for some time in order to extract and refine natural products. The properties of the components and phases involved in these processes under near critical conditions were only recently investigated more closely. The knowledge gained opened up possible ways of using dense gases in other processes too. This also includes the use in medical technology for the pulmonary application of drugs.
U.S. Pat. No. 5,301,664 describes a technique that can be used to produce various active ingredients as a fine mist by means of compressed carbon dioxide. These substances are first dissolved in the supercritical carbon dioxide, which is present as a single phase, under a pressure of 200 bar at a temperature close to the body temperature similar to an extraction process. Sudden expansion upon emerging from a nozzle into the surroundings causes fine pharmaceutical particles to be formed by condensation as a result of the solvent's reduced dissolving capacity. Use of a supercritical propellant medium does, however, also entail considerable disadvantages, particularly high outlay in terms of apparatus. The low solvency of carbon dioxide and the very high pressures needed in spite of potentially using an entrainer cause such an atomizer to have large dimensions. The pressure has to be maintained so as to prevent condensation in the pressure chamber, which would inevitably arise during discharge. This occurs by means of a mobile pressure chamber base, whose side facing away from the pressure chamber communicates with another compressed gas. This compressed gas has a sufficiently high vapor pressure. Nitrogen is e.g. used. In accordance with safety requirements, the compressed gas must be stored in gas cylinders which have to be carried along. A hand-held device is therefore out of the question. The withdrawal of active ingredient is regulated by a manually operated valve. The withdrawn drug dosage is therefore determined by the duration of opening. It is also complicated, in technical terms, to charge the components, i.e. fill up the atomizer.
The pharmaceutical aerosol formulations in the prior art consequently need to be improved, especially with regard to the propellant. The present invention's object is therefore to provide improved and environmentally friendly propellants and aerosol formulations which contain them. According to the invention, the micronization of drugs for pulmonary administration is to be particularly realized by means of dense gases, though avoiding halogenated hydrocarbons. The pharmaceutical particles generated in this way are to be easily respirable, i.e. exhibit as small a particle size as possible. Handling and outlay in terms of apparatus are also to be relatively simple, for which purpose the drugs are to be micronized in moderate conditions, i.e. at a low pressure and temperature (room temperature) and with conventional nozzle shapes.
It is known that some pharmaceuticals are soluble in liquid dimethyl ether, propane, butane and other hydrocarbons. The vapor pressures of these propellant gases at room temperature are in the range of up to approx. 10 bar. This property makes them suitable for an aerosol formulation, but a crucial problem lies in their very considerable evaporation enthalpy. When such a formulation is sprayed, the propellant gas does not evaporate sufficiently quickly. The drug therefore cannot be micronized very finely, which impedes the pharmaceutical's respirability.
The evaporation enthalpy of several other gases, such as carbon dioxide, sulfur hexafluoride and ethane, is much smaller. But they generally have a very poor dissolving capacity and a relatively high vapor pressure. As already mentioned above, a pressure of 200 bar or more is e.g. necessary when an appreciable amount of the drug is dissolved in supercritical carbon dioxide. For this reason, carbon dioxide and sulfur hexafluoride are equally unsuitable as propellant gases for a reasonable and economically beneficial aerosol formulation.